A number of studies have confirmed that bones and soft tissues such as ligaments and tendons, especially in adult persons, have a limited self-repairing capacity.
The functional and structural properties of tendons and of ligaments are very similar. Tendons are anatomical structures attaching muscles to bones and ligaments are similar structures attaching bones to other bones. Both are cylindrical, elongated structures, formed from dense connective tissue and adapted to tension in one direction, with parallel collagen (mainly type I collagen) fibers. The reduced vascularization of said tissues is one of the causes of the slow healing of tendons and ligaments.
The predominant cells in tendons are called tenocytes. The function of tenocytes is to maintain the matrix structure through degradation and synthesis processes. However, tendons have a relatively low cell density and with little mitotic activity, which explains the reduced rate of replacement of this tissue and questions the degree in which these cells can promote intrinsic healing.
Tendon injuries are the commonest orthopedic injuries. For example, at least 100,000 Achilles tendon injuries are diagnosed and treated yearly in USA (A. Praemer et al., “Musculoskeletal condition in the United States”, 1st ed. American Academy of Orthopaedic Surgeons, Park Ridge, Ill., 1992). It was also estimated that there were from 150,000 to 200,000 anterior cruciate ligament (ACL) injuries every year in the USA (S. L. Woo et al., “Contribution of biomechanics, orthopaedics and rehabilitation: the past present and future”, Surgeon 2(3), 125-136 (2004)).
Damages in tendons and ligaments are caused by different factors, including injuries due to practicing sports or accidents, distensions, incorrect postures, bacterial infections, adverse drug reactions, arthritis in a joint, and as a result of different diseases.
The healing below the optimal level, the long rehabilitation period and a high incidence of relapse make it difficult to suitably treat tendon and ligament injuries.
The most frequent pharmacological treatments for tendinopathies (tendon diseases) and desmopathies (ligament diseases) include the following: rest, physical therapy (exercises, massages, ultrasound, laser, hydrotherapy, heat and cold), dietary supplements, surgery and medicaments, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and antibiotics, the latter in the event that the disease has been caused by an infection. It is known that both NSAIDs and glucocorticoids have side-effects. The side-effects of NSAIDs include stomach acidity, nausea, diarrhea, dizziness and in some cases, gastric ulcers and liver inflammation. The side-effects of glucocorticoids can be bleeding, tendon rupture and infection, and can even slow down collagen synthesis. Furthermore, recent publications question the efficacy of NSAIDs in tendon regeneration (D. Marsolais et al., “Nonsteroidal anti-inflammatory drug reduces neutrophil and macrophage accumulation but does not improve tendon regeneration”, Lab. Invest. 83(7), 991-999 (2003)).
In the last few years, investigations are being conducted on the treatment of tendinopathies and desmopathies with stem cells (R. G. Young et al., “Use of mesenchymal stem cells in a collagen matrix for Achilles tendon repair”, J. Orthop. Res. 16(4), 406-413 (1998)), tenocytes (US 2005060033), ligament cells (J. A. Cooper, Jr., “Evaluation of the anterior cruciate ligament, medial collateral ligament, Achilles tendon and patellar tendon as cell sources for tissue-engineered ligament”, Biomaterials 27, 2747-2754 (2006)), growth factors (WO 01/82951; L. A. Dahlgren et al., “Insulin-like growth factor-I improves cellular and molecular aspects of healing in a collagenase-induced model of flexor tendonitis”, J. Orthop. Res. 20, 910-919 (2002)) or with genes (R. S. Goomer et al., “Nonviral in vivo gene therapy for tissue engineering of articular cartilage and tendon repair”, Clin. Orthop. Oct (379 Suppl), S189-200 (2000)).
Bone tissue is a specialized connective tissue which, like the rest of connective tissues, is formed by cells, fibers and ground substance but, unlike the others, its extracellular components are calcified and make it a hard, firm material which is suitable for its support and protection function. It provides internal support to the body and offers insertion sites to muscles, tendons and ligaments which are essential for movement.
Bone defects represent a great medical and socioeconomic challenge. For example, the most recent investigations include the application of different types of biomaterials for reconstructing damaged bone tissues (U. Kneser, et al., Tissue engineering of bone: the reconstructive surgeon's point of view, J. Cell. Mol. Med. 10 (1), 7-19 (2006)), as well as the use of growth factors (WO 2006/044334) and stem cells (U.S. Pat. No. 6,863,900).
Bones, tendons and ligaments, mentioned above, are components of the musculoskeletal system, and all of them are derived at an embryonic level from the mesoderm.
The compounds of the present invention are disaccharides described for the first time in patent EP 1300411 (U.S. Pat. No. 6,680,304), with usefulness in the treatment of the osteoarthritis (arthrosis). Said patent document also mentions their usefulness in the treatment of inflammatory diseases such as inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, rheumatic fever, palindromic rheumatism, Reiter's syndrome, lupus erythematosus and ankylosing spondylitis, as well as in blood coagulation control. The basic structure of these compounds contains the monosaccharides glucuronic acid and glucosamine, bonded by means of β-(1→3) bonds, and with a sulphate group in C-4 and/or in C-6 of the monosaccharide glucosamine.
Glycosaminoglycans (GAG) forming part of some compositions of the present invention are polymeric biomolecules with a high molecular weight which are essentially located in live organisms, in which they develop different physiological functions.
Chondroitin sulphate is a natural sulphated glycosaminoglycan with a polymeric structure characterized by a disaccharide which is repeated, formed by N-acetyl-D-galactosamine and D-glucuronic acid. Most of the N-acetyl-D-galactosamine residues are sulphated. Chondroitin sulphate is an essential component of the aggrecan which is located in articular cartilage.
The use of chondroitin sulphate for treating different diseases, for example in the treatment of cardiovascular diseases (U.S. Pat. No. 3,895,106) or in the treatment of psoriasis (WO2005/014012), has been described, however, its most extended use is in the treatment of osteoarthritis, which is characterized by the degeneration of hyaline articular cartilage (M. G. Lequesne, Rev. Rhum. Eng. Ed., 61, 69-73 (1994); G. Verbruggen et al., Osteoarthritis Cart., 6 (Supplement A), 37-38 (1998)).
Hyaluronic acid is a non-sulphated glycosaminoglycan with a polymeric structure characterized by a disaccharide which is repeated, formed by the monosaccharides N-acetyl-D-glucosamine and D-glucuronic acid. It is one of the main components of cartilage, of the synovial membrane and of synovial fluid. Its use in the treatment of osteoarthritis, generally intra-articularly, is particularly important. Its use in ophthalmology for speeding up wound healing, as well as in cosmetics, has also been described.
Contradictory results have been published on the use of chondroitin sulphate, of chondroitin polysulphate and of hyaluronic acid in the treatment of tendinopathies. Although some authors describe the beneficial effect of said compounds (E. M. Gaughan et al., “Effects of sodium hyaluronate on tendon healing and adhesion formation in horses”, Am. J. Vet. Res. 52(5), 764-773 (1991); H. Sundqvist et al., “A promising novel therapy for Achilles peritendinitis”, Int. J. Sports Med. 8, 298-303 (1987)), other authors, however, do not find significant differences between treated tendons and the control group (S. J. Dyson, “Medical management of superficial digital flexor tendonitis: a comparative study in 219 horses (1992-2000)”, Equine Vet. J. 36(5), 415-419 (2004); J. W. Foland et al., “Effect of sodium hyaluronate in collagenase-induced superficial digital flexor tendinitis in horses”, Am. J. Vet. Res. 53(12), 2371-2376 (1992)).
Inulin polysulphate, forming part of the compositions of the invention, is obtained from the natural polysaccharide inulin. The alkaline salts of inulin sulphate with different degrees of sulphation have been applied in the chemical industry as thickeners, adhesives and as additives for muds used in oil well drilling. It has been described that inulin sulphate has an anticoagulant (Arkiv for kemi, mineralogi o. geologi., Bd 24B (5), 1-4 (1946)) and antilipidemic activity (Arch. Int. Pharmacodyn, XCIX, 334 (1954)).
It has been described that inulin polysulphate (U.S. Pat. No. 4,021,545) has a complement inhibitory activity; therefore it could be used in the treatment of diseases such as rheumatoid arthritis, systemic lupus erythematosus and certain types of vasculitis. Its use in the treatment of osteoarthritis has also been described (WO 2005/084610).
According to the above, it was necessary to provide an alternative drug useful in the treatment or prevention of a tendon, ligament or bone disease, disorder or injury.
The use of the disaccharides of the present invention in the treatment of tendons, ligaments or bones has not been described up until now.
The compositions of the present invention comprising the disaccharides have not been described either.